Role of suppressors of cytokine signaling SOCS-1 and SOCS-3 in hepatic steatosis and the metabolic syndrome
Introduction
The metabolic syndrome is a disease complex composed of diabetes, hypertension, atherosclerosis, hyperlipidemia and nonalcoholic steatohepatitis, the topic of this symposium. Many lines of evidence accumulating have shown that there is a tight association between the metabolic syndrome and obesity. Both of them are usually accompanied by chronic inflammation and increased proinflammatory cytokines, such as TNFα and IL-6. It has also been revealed that adipose tissue is not only an energy-storage apparatus, but also functions as an endocrine organ secreting a variety of bioactive substances [1], namely adipokines or adipocytokines, including proinflammatory cytokines, such as TNFα and IL-6 (Fig. 1).
A recently proposed and widely accepted model for the mechanism by which obesity induces the metabolic syndrome is following [2]. In obesity, enlarged adipocytes recruit macrophages at adipose tissue and they activate each other. Then, the enlarged adipocytes are stimulated to secrete the different set of the adipokines from those released from the small adipocytes that maintain normal glucose/lipid metabolism. These adipokines released from the enlarged adipocytes modulate glucose/lipid metabolism, energy expenditure and vessel tone at various tissues, resulting in the development of the metabolic syndrome.
Especially in liver, the metabolic changes produced by the adipokines, exacerbate the disorders in other tissues by decreasing insulin clearance and overproduction of glucose and lipids. Thus, it is important to understand the molecular mechanism of the adipokine-mediated impairment of normal glucose and lipid metabolism in liver, although it still remains largely unexplored.
Section snippets
Increased SOCS proteins in liver cause systemic insulin resistance
As one of the candidates of the molecular link between the metabolic disorders and the adipokines, especially proinflammatory cytokine, we hypothesized that the SH2-containing adaptor proteins, suppressor of cytokine signaling SOCS-1 and SOCS-3, which were originally identified as negative regulators of Jak/STAT signaling [3], would play a role in the metabolic syndrome induced by obesity [4], [5]. Indeed, in livers of obese diabetic db/db mice, the levels of SOCS-1 and SOCS-3 mRNA and proteins
Amelioration of insulin resistance by suppressing SOCS-1 and SOCS-3 in db/db mouse
To directly address whether SOCS-1 and SOCS-3 contribute to the insulin resistance, hepatic steatosis and other metabolic derangement in obese diabetic animals, we treated db/db mice with antisense oligonucleotides against SOCS-1 and SOCS-3 (AS1 and AS3). Following 2 weeks of treatment with specific antisense oligonucleotides, there was a marked and specific down-regulation of the elevated levels of the expression of the targeted SOCS mRNA. Combination therapy (AS1 + AS3) reduced the expression
Improvement of hepatic steatosis and reduction of plasma triglyceride concentrations by suppressing SOCS-1 and SOCS-3
The most striking effects of SOCS antisense treatment in the db/db mice were on two other aspects of the metabolic syndrome, hepatic steatosis and hyperlipidemia, which aggravate hyperinsulinemia and insulin resistance. Thus, control db/db mice exhibited severe hepatic steatosis with a 5.8-fold increase in triglyceride content in liver and more than a doubling of fasting plasma triglyceride levels compared to the wild-type mice (Fig. 9). Antisense treatment, especially with AS3 and AS1 + AS3,
SOCS-1 and SOCS-3 enhance SREBP-1c promoter activity that is down-regulated by STAT3
The mechanism of up-regulation of SREBP-1c expression in insulin-resistant states is poorly understood, although insulin has been suggested to increase SREBP-1c expression in vivo. To address how SOCS proteins regulate SREBP-1c expression, we assessed promoter activity of SREBP-1c using well-differentiated Fao rat hepatoma cells. We found that expression of SOCS-1 or SOCS-3 enhanced SREBP-1c promoter activity (Fig. 11) at a time when these same SOCS proteins inhibit insulin signaling,
Conclusions
Recently, Kasuga and coworkers have shown that liver-specific STAT3 knockout causes marked increases in SREBP-1 expression and hepatic triglyceride content and that adenoviral-mediated gene transfer of a constitutively active form of STAT3 in liver of db/db mouse ameliorates hepatic steatosis with down-regulation of SREBP-1 expression [8]. Together with our data, this indicates the importance of SOCS proteins and STAT3 in the regulation of lipid synthesis in liver and a paradigm for integrating
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2022, Molecular MetabolismCitation Excerpt :As expected, mice HF-fed for 20 weeks displayed accumulation and expansion of lipid droplets in hepatocytes (Figure 5A) and increased triglyceride content (Figure 5B) for both genotypes, which was enhanced in IL-6Ra KD mice (p < 0.01 vs Cre+/- HF, p < 0.001 vs KD SC). There was no detectable difference in liver IL-6Ra expression from IL-6Ra KD and Cre+/- mice on either diet (Figure 5C), likewise transcript abundance of Socs3, liver levels of which have been suggested to play an important role in steatosis [41–43], was unaltered by either diet or genotype (Figure 5D). In addition, HF-fed IL-6Ra KD mice exhibited an increase in Igfbp1 (Figure 5E), a predictive marker for liver lipid accumulation [44].
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